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  • Till date the first line treatment of

    2022-01-18

    Till date, the first line treatment of T2DM is oral metformin followed by oral sulfonylureas, dipeptidyl peptidase-IV-inhibitors, and TZDs. As the disease progresses, injectable glucagon-like peptide-I analogues or ultimately insulin become necessary to maintain glycaemic control. Despite the established guidelines, there is still no cure for T2DM. Additionally, many of the traditional current therapies are associated with gastro-intestinal discomforts (metformin), hypoglycaemia, and weight gain (sulfonylurea and to lesser extent meglitinides), or edema and increased risk of bone fractures (TZDs). In this regard, there has been an influx of novel antidiabetic agents influencing a variety of cellular targets. Recently, free fatty Calcein AM receptor-I (FFAR1) has emerged as a promising target, belonging to the class A family of G-protein-coupled receptors (GPCRs). FFAR1 is mainly expressed in the pancreatic β-cells, and to a lesser extent in gastrointestinal enteroendocrine cells, immune cells, and parts of the brain., , This lipid-binding receptor enhances glucose-stimulated insulin secretion (GSIS) by direct action on β-cells and possibly indirectly through the incretin system. Since FFAR1-induced GSIS is glucose-dependent, FFAR1’s mechanism potentially mitigates the risk of hypoglycemia seen with standard insulin secretagogues., In our recent publication, we described the discovery of novel hybrid molecules possessing a balanced dual agonism on PPAR-γ and FFAR1 receptors. These hybrids would act as insulin sensitizers and secretagogues through their action on PPAR-γ and FFAR1, respectively. Unlike marketed secretagogues/sensitizers combination; Amaryl M™ (metformin/glimepiride) and glucovance™ (metformin/glibenclamide), these hybrids could provide less complex pharmacokinetic/pharmacodynamic relationships. Such profiles would lead to more predictable variability between patients and less extensive clinical studies. Additionally, the afforded moderate activity of these hybrids, down to one digit μM, could be beneficial to limit the potential adverse effects raised with potent PPAR-γ agonists. Nevertheless, such hybrids could keep an acceptable overall anti-diabetic efficacy as a result of their collective synergism on both receptors. The design of our lead compounds depends on combining the 5-benzyl-thiazolidinedione scaffold, as TZDs common pharmacophore, with diverse GPCRs’ privileged structures, as hydrophobic tails, through a simple alkyl linker (). In another previous study, we illustrated through homology modelling and molecular dynamics simulations that the TZD acidic head is capable of binding to the critical polar residues within both PPAR-γ and FFAR1 binding domains. The biphenyl, phenoxybenzyl, and benzimidazole-based derivatives represent excellent choices as versatile hydrophobic tails (series , - and -; ). Such choice was based on preliminary molecular docking studies conducted in our late publication. These three scaffolds showed preferential binding, with both receptors, out of a total 17 docked GPCRs’ privileged structures. Notably, our rationalized design came in great consistency with a recently published mini-review article by Yasmin et al., summarizing the chemical modifications around TZDs in past two decades. Through extensive mining, the authors depicted that the 5-[4-alkyloxybenzyl]-thiazolidinedione scaffold, being adopted herein, is considered an optimal motif for furnishing favourable PPAR-γ transactivation. Regarding our preliminary study, eight compounds showed balanced agonistic activity on both PPAR-γ and FFAR1 receptors. Both the benzimidazole series and biphenyl series , ranked second in activity, were proved to be the most suitable scaffolds for this purpose. Assessment of activity was done using luciferase bioluminescence and calcium flux/fluorometric imaging plate reader (FLIPR) assays for PPAR-γ and FFAR1 transactivation, respectively. High intrinsic activities were noticed, with significantly larger maximum fold-induction compared to that of the PPAR-γ full agonist reference, rosiglitazone.